چکیده انگلیسی

Abstract
In simple systems, lifespan can be extended by various methods including dietary restriction, mutations in the insulin/insulin-like growth factor (IGF) pathway or mitochondria among other processes. It is widely held that the mechanisms that extend lifespan may be adapted for diminishing age-associated pathologies. We tested whether a number of compounds reported to extend lifespan in C. elegans could reduce age-dependent toxicity caused by mutant TAR DNA-binding protein-43 in C. elegans motor neurons. Only half of the compounds tested show protective properties against neurodegeneration, suggesting that extended lifespan is not a strong predictor for neuroprotective properties. We report here that resveratrol, rolipram, reserpine, trolox, propyl gallate, and ethosuximide protect against mutant TAR DNA-binding protein-43 neuronal toxicity. Finally, of all the compounds tested, only resveratrol required daf-16 and sir-2.1 for protection, and ethosuximide showed dependence on daf-16 for its activity.

مقدمه انگلیسی

1. Introduction
For more than 75 years, people have been fascinated by the discovery that rats living on a restricted diet (dietary restriction) showed increased lifespan (McCay et al., 1989), a phenomenon that is under investigation in primates (Colman et al., 2009; Mattison et al., 2012). Of great interest is the fact that not only do many organisms show increased lifespan under dietary restriction conditions but they also show decreased incidences of age-related pathologies (Anderson and Weindruch, 2012). Additional mechanisms that regulate longevity have been discovered including mitochondrial function and the insulin/insulin-like growth factor (IGF) signaling pathway. Molecular and genetic approaches have begun to decipher the cellular mechanisms of lifespan extension and this has led to the development of an industry hoping to find and develop longevity mimetics as potential therapeutic agents against age-related disease (Mercken et al., 2012). Work from model organisms like C. elegans has identified numerous compounds that extend lifespan by influencing conserved longevity mechanisms and we wondered if these compounds would be effective against age-dependent proteotoxicity. To evaluate these compounds we turned to a C. elegans model of age-dependent motor neuron toxicity ( Vaccaro et al., 2012a) and tested 11 compounds reported to extend lifespan. We identified 6 compounds that reduced mutant transactive response (TAR) DNA-binding protein-43 (TDP-43) neuronal toxicity and might be useful as candidates for testing and drug development in mammalian models of neurodegeneration.